Transcriptome-Wide Analysis Identifies Novel Associations With Blood Pressure

Abstract

Hypertension represents a major cardiovascular risk factor. The pathophysiology of increased blood pressure (BP) is not yet completely understood. Transcriptome profiling offers possibilities to uncover genetics effects on BP. Based on 2 populations including 2549 individuals, a meta-analyses of monocytic transcriptome-wide profiles were performed to identify transcripts associated with BP. Replication was performed in 2 independent studies of whole-blood transcriptome data including 1990 individuals. For identified candidate genes, a direct link between long-term changes in BP and gene expression over time and by treatment with BP-lowering therapy was assessed. The predictive value of protein levels encoded by candidate genes for subsequent cardiovascular disease was investigated. Eight transcripts (<i>CRIP1</i>, <i>MYADM</i>, <i>TIPARP</i>, <i>TSC22D3</i>, <i>CEBPA</i>, <i>F12, LMNA</i>, and <i>TPPP3</i>) were identified jointly accounting for up to 13% (95% confidence interval, 8.7-16.2) of BP variability. Changes in <i>CRIP1</i>, <i>MYADM</i>, <i>TIPARP</i>, <i>LMNA</i>, <i>TSC22D3</i>, <i>CEBPA</i>, and <i>TPPP3</i> expression associated with BP changes-among these, <i>CRIP1</i> gene expression was additionally correlated to measures of cardiac hypertrophy. Assessment of circulating CRIP1 (cystein-rich protein 1) levels as biomarkers showed a strong association with increased risk for incident stroke (hazard ratio, 1.06; 95% confidence interval, 1.03-1.09; <i>P</i>=5.0×10^-5). Our comprehensive analysis of global gene expression highlights 8 novel transcripts significantly associated with BP, providing a link between gene expression and BP. Translational approaches further established evidence for the potential use of CRIP1 as emerging disease-related biomarker.